This invention relates to a group of cyclic sulfonamide compounds and derivatives that inhibit matrix metalloproteinase enzymes and thus are useful for treating diseases resulting from tissue breakdown, such as heart disease, multiple sclerosis, arthritis, atherosclerosis, and osteoporosis.
Matrix metalloproteinases (sometimes referred to as MMPs) are naturally occurring enzymes found in most mammals. Over-expression and activation of MMPs or an imbalance between MMPs and inhibitors of MMPs have been suggested as factors in the pathogenesis of diseases characterized by the breakdown of extracellular matrix or connective tissues.
Stromelysin-1 and gel atinase A are members of the MMP family. Other members include fibroblast collagenase (MMP-1), neutrophil collagenase (MMP-8), gelatinase B (92 kDa gelatinase) (MMP-9), stromelysin-2 (MMP-10), stromelysin-3 (MMP-11), matrilysin (MMP-7), collagenase 3 (MMP-13), TNF-alpha converting enzyme (TACE), and other newly discovered membrane-associated matrix metalloproteinases (Sato H., Takino T., Okada Y., Cao J., Shinagawa A., Yamamoto E., Seiki M., Nature, 1994;370:61-65). These enzymes have been implicated in a number of diseases which result from breakdown of connective tissue; including such diseases as rheumatoid arthritis, osteoarthritis, osteoporosis, periodontitis, multiple sclerosis, gingivitis, corneal epidermal and gastric ulceration, atherosclerosis, neointimal proliferation which leads to restenosis and ischemic heart failure, and tumor metastasis. A method for preventing and treating these and other diseases is now recognized to be by inhibiting metalloproteinase enzymes, thereby curtailing and/or eliminating the breakdown of connective tissues that results in the disease states.
The catalytic zinc in matrix metalloproteinases is typically the focal point for inhibitor design. The modification of substrates by introducing zinc chelating groups has generated potent inhibitors such as peptide hydroxamates and thiol-containing peptides. Peptide hydroxamates and the natural endogenous inhibitors of MMPs (TIMPs) have been used successfully to treat animal models of cancer and inflammation. MMP inhibitors have also been used to prevent and treat congestive heart failure and other cardiovascular diseases. For example, see U.S. Pat. No. 5,948,780.
The need to find new low-molecular weight compounds that are potent MMP inhibitors, and that have an acceptable therapeutic index of toxicity/potency to make them amenable for clinical use in the prevention and treatment of the associated disease states, continues. An object of this invention is to provide a group of MMP inhibitors characterized as being sulfonamides bearing a tricyclic aromatic or heteroaromatic substituent.
This invention provides a group of tricyclic substituted sulfonamide compounds that are inhibitors of matrix metalloproteinase enzymes. The invention is more particularly directed to compounds defined by Formula I 
or the pharmaceutically acceptable salts thereof wherein:
R1 and R2 independently are hydrogen or C1-C6 alkyl;
R3 and R4 independently are hydrogen, halo, nitro, NR5R6, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; (CH2)mOH, (CH2)mOR5, (CH2)m cycloalkyl, (CH2)m aryl, (CH2)m substituted aryl, (CH2)m heteroaryl, (CH2)m substituted heteroaryl, (CH2)m carbocycle, (CH2)m heterocycle; (CH2)m NR5R6, (CH2)mCOR5, (CH2)mCONR5R6, or (CH2)mCO2R5;
m is an integer from 0 to 6;
R5 and R6 independently are hydrogen or C1-C6 alkyl, or taken together with the nitrogen to which they are attached complete a 3- to 7-membered ring;
Z is (CH2)n;
n is 0, 1, or 2;
Y is S, SO, or SO2;
X is OH or NHOH;
V is O, S, SO2, NH, NR5, or CH2.
Another invention embodiment is a compound of Formula II 
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, V, and X are as defined above.
Another invention embodiment is a compound of Formula II, or a pharmaceutically acceptable salt thereof, wherein R3 is halo.
Another invention embodiment is a compound of Formulas I or II, or a pharmaceutically acceptable salt thereof, wherein X is OH.
Another invention embodiment is a compound of Formulas I or II, or a pharmaceutically acceptable salt thereof, wherein X is NHOH.
Another invention embodiment is a compound of Formula III 
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and X are as defined above.
Another invention embodiment is a compound of Formula IV 
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and X have the above defined meanings.
Another invention embodiment is a compound of Formula V 
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and X are as defined above.
Another invention embodiment is a compound of Formula VI 
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and X are as defined above.
Another invention embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Y is SO2.
Another invention embodiment is a compound of Formula VII 
or a pharmaceutically acceptable salt thereof, wherein V, Z, X, R1, and R2 are as defined above for Formula I.
A further embodiment of this invention is a pharmaceutical composition, comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, admixed with a pharmaceutically acceptable carrier, excipient, or diluent.
Another invention embodiment is a pharmaceutical composition, comprising a compound of any one of Formulas II through VII, or a pharmaceutically acceptable salt thereof, admixed with a pharmaceutically acceptable carrier, excipient, or diluent.
Another invention embodiment is a pharmaceutical composition, comprising a compound selected from:
(S)-4-(Dibenzofuran-3-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid;
(S)-4-(Dibenzofuran-3-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
R-3-(Dibenzofuran-3-sulfonyl)-5,5-dimethyl-thiazolidine-4-carboxylic acid;
R-3-(Dibenzofuran-3-sulfonyl)-5,5-dimethyl-thiazolidine-4-carboxylic acid hydroxyamide;
(S)-4-(9H-Fluorene-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid;
(S)-4-(9H-Fluorene-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
(S)-4-(Dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid;
(S)-4-(Dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
(S)-4-(7-Bromo-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid;
(S)-4-(7-Bromo-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
(S)-4-(7-Methoxycarbonyl-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid;
(S)-4-(7-Methoxycarbonyl-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
(S)-2,2-Dimethyl-4-(7-nitro-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylic acid;
(S)-2,2-Dimethyl-4-(7-nitro-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylic acid hydroxyamide;
(S)-4-(Dibenzofuran-2-sulfonyl)-2,2-dimethyl-1,1-dioxo-thiomorpholine-3-carboxylic acid hydroxyamide;
(S)-4-(7-Isobutyrylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid;
(S)-2,2-Dimethyl-4-[7-(3-phenyl-propionylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylic acid;
(S)-2,2-Dimethyl-4-[7-(4-methyl-pentanoylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylic acid;
(S)-4-(7-Benzoylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid;
(S)-2,2-Dimethyl-4-(7-propionylamino-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylic acid;
(S)-4-[7-(3-Ethyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylic acid;
(S)-4-[7-(3-Isopropyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylic acid;
(S)-2,2-Dimethyl-4-[7-(3-phenyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylic acid;
(S)-4-[7-(3,3-Diethyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylic acid;
(S)-4-[7-(2,4-Dichloro-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carbxoylic acid hydroxyamide;
(S)-4-[7-(3,4-Dimethoxy-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
(S)-4-[7-(2,5-Dimethoxy-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
(S)-2,2-Dimethyl-4-(7-phenylacetylamino-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylic acid hydroxyamide;
(S)-2,2-Dimethyl-4-{7-[(thiophene-2-carbonyl)-amino]-dibenzofuran-2-sulfonyl}-thiomorpholine-3-carboxylic acid hydroxyamide;
(S)-4-[7-(3-Ethyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
(S)-4-[7-(3-Isopropyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
(S)-2,2-Dimethyl-4-[7-(3-phenyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
(S)-4-[7-(3,3-Diethyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
2,2-Dimethyl-4-[7-(3-nitro-benzoylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylic acid hydroxyamide;
4-(7-Dodecanoylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
N-[8-(3-Hydroxycarbamoyl-2,2-dimethyl-thiomorpholine-4-sulfonyl)-dibenzofuran-3-yl]-oxalamic acid ethyl ester;
4-[7-(Cyclohexanecarbonyl-amino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
4-[7-(2-Fluoro-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
4-(7-Acetylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
Acetic acid 2-[8-(3-hydroxycarbamoyl-2,2-dimethyl-thiomorpholine-4-sulfonyl)-dibenzofuran-3-ylcarbamoyl]-phenyl ester;
4-(7-Benzoylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
4-(7-Butyrylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
4-(7-Decanoylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
4-(7-Decanoylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
4-(7-Diphenylacetylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
4-{7-[2-(4-Chloro-phenoxy)-acetylamino]-dibenzofuran-2-sulfonyl}-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
N-[8-(3-Hydroxycarbamoyl-2,2-dimethyl-thiomorpholine-4-sulfonyl)-dibenzofuran-3-yl]-succinamic acid methyl ester;
4-[7-(3,4-Dimethoxy-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
4-[7-(2-Methoxy-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
4-[7-(2,2-Dimethyl-pentanoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
4-[7-(2,4-Dichloro-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
4-[7-(2,5-Dimethoxy-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
2,2-Dimethyl-4-[7-(4-methyl-pentanoylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylic acid hydroxyamide;
4-[7-(Cyclopropanecarbonyl-amino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
Acetic acid [8-(3-hydroxycarbamoyl-2,2-dimethyl-thiomorpholine-4-sulfonyl)-dibenzofuran-3-ylcarbamoyl]-phenyl-methyl ester;
2,2-Dimethyl-4-{7-[(tricyclo[3.3.1]decanane-1-carbonyl)-amino]-dibenzofuran-2-sulfonyl}-thiomorpholine-3-carboxylic acid hydroxyamide;
2,2-Dimethyl-4-(7-pentanoylamino-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylic acid hydroxyamide;
4-[7-(2,2-Dimethyl-propionylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
2,2-Dimethyl-4-[7-((Z)-octadec-9-enoylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylic acid hydroxyamide;
N-[8-(3-Hydroxycarbamoyl-2,2-dimethyl-thiomorpholine-4-sulfonyl)-dibenzofuran-3-yl]-succinamic acid ethyl ester;
4-(7-Isobutyrylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
4-(7-Isobutyrylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
4-[7-(3-Chloro-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
2,2-Dimethyl-4-(7-nonanoylamino-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylic acid hydroxyamide;
2,2-Dimethyl-4-[7-(2-trifluoromethyl-benzoylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylic acid hydroxyamide;
2,2-Dimethyl-4-[7-(2-trifluoromethyl-benzoylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylic acid hydroxyamide;
2,2-Dimethyl-4-(7-octanoylamino-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylic acid hydroxyamide;
4-(7-Hexadecanoylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
4-(7-Hexadecanoylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
2,2-Dimethyl-4-[7-(2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluoro-octanoylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylic acid hydroxyamide;
2,2-Dimethyl-4-[7-(2-phenoxy-acetylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylic acid hydroxyamide;
2,2-Dimethyl-4-[7-(2-phenoxy-acetylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylic acid hydroxyamide;
2,2-Dimethyl-4-(7-phenylacetylamino-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylic acid hydroxyamide;
2,2-Dimethyl-4-(7-propionylamino-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylic acid hydroxyamide;
2,2-Dimethyl-4-(7-tridecanoylamino-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylic acid hydroxyamide;
4-[7-(3,5-Dinitro-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
N-[8-(3-Hydroxycarbamoyl-2,2-dimethyl-thiomorpholine-4-sulfonyl)-dibenzofuran-3-yl]-malonamic acid ethyl ester;
N-[8-(3-Hydroxycarbamoyl-2,2-dimethyl-thiomorpholine-4-sulfonyl)-dibenzofuran-3-yl]-malonamic acid ethyl ester;
2,2-Dimethyl-4-[7-(2,2,2-trichloro-acetylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylic acid hydroxyamide;
2,2-Dimethyl-4-{7-[(thiophene-2-carbonyl)-amino]-dibenzofuran-2-sulfonyl}-thiomorpholine-3-carboxylic acid hydroxyamide;
2,2-Dimethyl-4-[7-(3-phenyl-propionylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylic acid hydroxyamide; and
4-[7-(2-Bromo-benzoylamino)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide, or a pharmaceutically acceptable salt thereof, admixed with a pharmaceutically acceptable carrier, diluent, or excipient.
Another embodiment of this invention is a method for inhibiting MMP enzymes in an animal, comprising administering to the animal an MMP inhibiting amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
A further embodiment is a method for treating a disease mediated by an MMP enzyme, comprising administering to a patient suffering from such disease an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Another invention embodiment is a method for treating a cancer, comprising administering to a patient suffering from such a disease an anticancer effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Another invention embodiment is a method for treating breast carcinoma, comprising administering to a patient suffering from such a disease an anticancer effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Another invention embodiment is a method for treating a rheumatoid arthritis, comprising administering to a patient suffering from such a disease an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Another invention embodiment is a method for treating a osteoarthritis, comprising administering to a patient suffering from such a disease an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Another invention embodiment is a method for treating a heart failure, comprising administering to a patient suffering from such a disease an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Another invention embodiment is a method for treating a inflammation, comprising administering to a patient suffering from such a disease an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Another embodiment of this invention is use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease mediated by an MMP enzyme.
Another invention embodiment is use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.
Another invention embodiment is use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of arthritis.
Another invention embodiment is use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of rheumatoid arthritis.
Another invention embodiment is use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of osteoarthritis.
Another invention embodiment is use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of congestive heart failure.
The compounds provided by this invention are those defined by Formula I. In Formula I, R1-R4 include xe2x80x9cC1-C6 alkylxe2x80x9d groups. These are straight and branched carbon chains having from 1 to 6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, isopropyl, tert.-butyl, neopentyl, and n-hexyl. The alkyl groups can be substituted if desired, for instance with groups such as hydroxy, amino, alkyl, and dialkylamino, halo, trifluoromethyl, carboxy, nitro, and cyano.
xe2x80x9cHaloxe2x80x9d includes fluoro, chloro, bromo, and iodo.
xe2x80x9cAlkenylxe2x80x9d means straight and branched hydrocarbon radicals having from 2 to 6 carbon atoms and one double bond and includes ethenyl, 3-buten-1-yl, 2-ethenylbutyl, 3-hexen-1-yl, and the like.
xe2x80x9cAlkynylxe2x80x9d means straight and branched hydrocarbon radicals having from 2 to 6 carbon atoms and 1 triple bond and includes ethynyl, 3-butyn-1-yl, propynyl, 2-butyn-1-yl, 3-pentyn-1-yl, and the like.
xe2x80x9cCycloalkylxe2x80x9d means a monocyclic or polycyclic hydrocarbyl group such as cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl, norpinanyl, decalinyl, norbornyl, cyclohexyl, and cyclopentyl. Such groups can be substituted with groups such as hydroxy, keto, and the like. Also included are rings in which 1 to 3 heteroatoms replace carbons. Such groups are termed xe2x80x9cheterocyclylxe2x80x9d, which means a cycloalkyl group also bearing at least one heteroatom selected from O, S, or NR2, examples being oxiranyl, pyrrolidinyl, piperidyl, tetrahydropyran, and morpholine.
xe2x80x9cAlkoxyxe2x80x9d refers to the alkyl groups mentioned above bound through oxygen, examples of which include methoxy, ethoxy, isopropoxy, tert-butoxy, and the like. In addition, alkoxy refers to polyethers such as xe2x80x94Oxe2x80x94(CH2)2xe2x80x94Oxe2x80x94OH3, and the like.
xe2x80x9cAlkanoylxe2x80x9d groups are alkyl linked through a carbonyl, i.e., C1-C5xe2x80x94C(O)xe2x80x94. Such groups include formyl, acetyl, propionyl, butyryl, and isobutyryl.
xe2x80x9cAcylxe2x80x9d means an alkyl or aryl (Ar) group bonded through a carbonyl group, i.e., Rxe2x80x94C(O)xe2x80x94, where R is alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, all optionally substituted. For example, acyl includes a C1-C6 alkanoyl, including substituted alkanoyl, wherein the alkyl portion can be substituted by NR5R6 or a carboxylic or heterocyclic group. Typical acyl groups include acetyl, benzoyl, and the like.
The alkyl, alkenyl, alkoxy, and alkynyl groups described above are optionally substituted, preferably by 1 to 3 groups selected from NR5R6, phenyl, substituted phenyl, thio C1-C6 alkyl, C1-C6 alkoxy, hydroxy, carboxy, C1-C6 alkoxycarbonyl, halo, nitrile, cycloalkyl, and a 5- or 6-membered carbocyclic ring or heterocyclic ring having 1 or 2 heteroatoms selected from nitrogen, substituted nitrogen, oxygen, and sulfur. xe2x80x9cSubstituted nitrogenxe2x80x9d means nitrogen bearing C1-C6 alkyl or (CH2)nPh where n is 1, 2, or 3. Perhalo and polyhalo substitution is also embraced.
Examples of substituted alkyl groups include 2-aminoethyl, pentachloroethyl, trifluoromethyl, 2-diethylaminoethyl, 2-dimethylaminopropyl, ethoxycarbonylmethyl, 3-phenylbutyl, methanylsulfanylmethyl, methoxymethyl, 3-hydroxypentyl, 2-carboxybutyl, 4-chlorobutyl, 3-cyclopropylpropyl, pentafluoroethyl, 3-morpholinopropyl, piperazinylmethyl, and 2-(4-methylpiperazinyl)ethyl.
Examples of substituted alkynyl groups include 2-methoxyethynyl, 2-ethylsulfanyethynyl, 4-(1-piperazinyl)-3-(butynyl), 3-phenyl-5-hexynyl, 3-diethylamino-3-butynyl, 4-chloro-3-butynyl, 4-cyclobutyl-4-hexenyl, and the like.
Typical substituted alkoxy groups include aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy, 6-carboxhexyloxy, and the like.
Further, examples of substituted alkyl, alkenyl, and alkynyl groups include dimethylaminomethyl, carboxymethyl, 4-dimethylamino-3-buten-1-yl, 5-ethylmethylamino-3-pentyn-1-yl, 4-morpholinobutyl, 4-tetrahydropyrinidylbutyl, 3-imidazolidin-1-ylpropyl, 4-tetrahydrothiazol-3-yl-butyl, phenylmethyl, 3-chlorophenylmethyl, and the like.
As noted above, R4 and R5 include hydrogen, alkyl, and aryl. Examples of NR4R5 groups include amino, methylamino, di-isopropylamino, acetyl amino, propionyl amino, 3-aminopropyl amino, 3-ethylaminobutyl amino, 3-di-n-propylamino-propyl amino, 4-diethylaminobutyl amino, and 3-carboxypropionyl amino. R4 and R5 can be taken together with the nitrogen to which they are attached to form a ring having 3 to 7 carbon atoms and 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, substituted nitrogen, oxygen, and sulfur. Examples of such cyclic NR4R5 groups include pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl, pyridinyl, piperidinyl, pyrazinyl, morpholinyl, and the like.
The terms xe2x80x9cArxe2x80x9d and xe2x80x9carylxe2x80x9d refer to unsubstituted and substituted aromatic groups. Heteroaryl groups have from 4 to 9 ring atoms, from 1 to 4 of which are independently selected from the group consisting of O, S, and N. Preferred heteroaryl groups have 1 or 2 heteroatoms in a 5- or 6-membered aromatic ring. Mono- and bicyclic aromatic ring systems are included in the definition of aryl and heteroaryl. Typical aryl and heteroaryl groups include phenyl, 3-chlorophenyl, 2,6-dibromophenyl, pyridyl, 3-methylpyridyl, benzothienyl, 2,4,6-tribromophenyl, 4-ethylbenzothienyl, furanyl, 3,4-diethylfuranyl, naphthyl, 4,7-dichloronaphthyl, morpholinyl, indolyl, benzotriazolyl, indazolyl, pyrrole, pyrazole, imidazole, thiazole, and the like.
Preferred Ar groups are phenyl and phenyl substituted by 1, 2, or 3 groups independently selected from the group consisting of alkyl, alkoxy, thio, thioalkyl, halo, hydroxy, xe2x80x94COOR7, trifluoromethyl, nitro, amino of the formula xe2x80x94NR5R6, and T(CH2)mQR5 or T(CH2)mCO2R5 wherein m is 1 to 6, T is O, S, NR5, N(O)R5, NR5R6Z, or CR5R6, Q is O, S, NR5, N(O)R5, or NR4R5R6Y wherein R4, R5, and R6 are as described above, R7 is alkyl or substituted alkyl, for example, methyl, trichloroethyl, diphenylmethyl, and the like, and Z is a counter ion such as chloride or bromide. The alkyl and alkoxy groups can be substituted as defined above. For example, typical groups are carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, hydroxyalkoxy, and alkoxyalkyl.
The term xe2x80x9cpatientxe2x80x9d means a mammal. Preferred patients include humans, cats, dogs, cows, horses, pigs, and sheep.
The term xe2x80x9canimalxe2x80x9d means a mammal. Preferred animals include humans, rats, mice, guinea pigs, rabbits, monkeys, cats, dogs, cows, horses, pigs, and sheep.
The phrases xe2x80x9ctherapeutically effective amountxe2x80x9d and xe2x80x9ceffective amountxe2x80x9d are synonymous unless otherwise indicated, and mean an amount of a compound of the present invention that is sufficient to improve the condition, disease, or disorder being treated. Determination of a therapeutically effective amount, as well as other factors related to effective administration of a compound of the present invention to a patient in need of treatment, including dosage forms, routes of administration, and frequency of dosing, may depend upon the particulars of the condition that is encountered, including the patient and condition being treated, the severity of the condition in a particular patient, the particular compound being employed, the particular route of administration being employed, the frequency of dosing, and the particular formulation being employed. Determination of a therapeutically effective treatment regimen for a patient is within the level of ordinary skill in the medical or veterinarian arts. In clinical use, an effective amount may be the amount that is recommended by the United States Food and Drug Administration, or an equivalent foreign agency.
The phrase xe2x80x9cadmixedxe2x80x9d or xe2x80x9cin admixturexe2x80x9d means the ingredients so mixed comprise either a heterogeneous or homogeneous mixture. Preferred is a homogeneous mixture.
The phrases xe2x80x9cpharmaceutical preparationxe2x80x9d and xe2x80x9cpreparationxe2x80x9d are synonymous unless otherwise indicated, and include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component, with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Pharmaceutical preparations are fully described below.
The phrase xe2x80x9canticancer effective amountxe2x80x9d means an amount of invention compound, or a pharmaceutically acceptable salt thereof, sufficient to inhibit, halt, or cause regression of the cancer being treated in a particular patient or patient population. For example in humans or other mammals, an anticancer effective amount can be determined experimentally in a laboratory or clinical setting, or may be the amount required by the guidelines of the United States Food and Drug Administration, or equivalent foreign agency, for the particular cancer and patient being treated.
The phrase xe2x80x9cMMP-13 inhibiting amountxe2x80x9d means an amount of invention compound, or a pharmaceutically acceptable salt thereof, sufficient to inhibit an enzyme matrix metalloproteinase-13, including a truncated form thereof, including a catalytic domain thereof, in a particular animal or animal population. For example in a human or other mammal, an MMP-13 inhibiting amount can be determined experimentally in a laboratory or clinical setting, or may be the amount required by the guidelines of the United States Food and Drug Administration, or equivalent foreign agency, for the particular MMP-13 enzyme and patient being treated.
It should be appreciated that the matrix metalloproteinases include the following enzymes:
MMP-1, also known as interstitial collagenase, collagenase-1, or fibroblast-type collagenase;
MMP-2, also known as gelatinase A or 72 kDa Type IV collagenase;
MMP-3, also known as stromelysin or stromelysin-1;
MMP-7, also known as matrilysin or PUMP-1;
MMP-8, also known as collagenase-2, neutrophil collagenase, or polymorphonuclear-type (xe2x80x9cPMN-typexe2x80x9d) collagenase;
MMP-9, also known as gelatinase B or 92 kDa Type IV collagenase;
MMP-10, also known as stromelysin-2;
MMP-11, also known as stromelysin-3;
MMP-12, also known as metalloelastase;
MMP-13, also known as collagenase-3;
MMP-14, also known as membrane-type (xe2x80x9cMTxe2x80x9d) 1-MMP or MT1-MMP;
MMP-15, also known as MT2-MMP;
MMP-16, also known as MT3-MMP;
MMP-17, also known as MT4-MMP;
MMP-18; and
MMP-19.
Other MMPs are known, including MMP-26, which is also known as matrilysin-2.
The term xe2x80x9cIC50xe2x80x9d means the concentration of test compound required to inhibit activity of a biological target, such as a receptor or enzyme, by 50%.
The phrase xe2x80x9ca method for inhibiting MMP enzymesxe2x80x9d includes methods of inhibiting full-length MMP enzymes, truncated forms thereof that retain catalytic activity, including forms that contain the catalytic domains of the MMP enzymes, as well as the catalytic domains of the MMP enzymes alone, and truncated forms of the catalytic domains that retain at least some catalytic activity.
It should be appreciated that it has been shown previously (Ye Qi-Zhuang, et al., supra, 1996) that inhibitor activity against a catalytic domain of an MMP is predictive of the inhibitor activity against the respective full-length enzyme.
The compounds to be used in the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Several of the compounds have one or more chiral centers, and as such can exist as racemates and pure enantiomers. All optical isomers and positional isomers are included in the scope of this invention.
The compounds of Formulas I through VII are capable of further forming both pharmaceutically acceptable salts, including but not limited to acid addition and/or base salts, solvents and N-oxides of a compound of Formulas I through VII. This invention also provides pharmaceutical formulations comprising a compound of Formulas I through VII together with a pharmaceutically acceptable carrier, diluent, or excipient therefor. All of these forms can be used in the method of the present invention.
Pharmaceutically acceptable acid addition salts of the compounds of Formulas I through VII include salts derived form inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorus, and the like, as well as the salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Also contemplated are the salts of amino acids such as arginate, gluconate, galacturonate, and the like; see, for example, Berge et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. of Pharmaceutical Science, 1977;66:1-19.
The acid addition salts of the basic compounds are prepared by contacting the free-base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free-base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free-base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention.
Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or of organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine. For example, see Berge et al., supra, 1977.
The base addition salts of acidic compounds are prepared by contacting the free-acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free-acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free-acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention.
The compounds of the present invention can be formulated and administered in a wide variety of oral and parenteral dosage forms, including transdermal and rectal administration. All that is required is that an MMP inhibitor be administered to a mammal suffering from a disease in an effective amount, which is that amount required to cause an improvement in the disease and/or the symptoms associated with such disease. It will be recognized by those skilled in the art that the following dosage forms may comprise as the active component, either a compound of Formulas I through VII, or a corresponding pharmaceutically acceptable salt or solvate of a compound of Formulas I through VII.
A compound of Formula I, or a pharmaceutically acceptable salt thereof, may be prepared by one of ordinary skill in the art of organic chemistry by procedures found in the chemical literature such as, for example, Reagents for Organic Synthesis by Fieser and Fieser, New York: 2000, John Wiley and Sons, Inc.; Comprehensive Organic Transformations, by Richard C. Larock, VCH Publishers, Inc., New York, 1989; the series Compendium of Organic Synthetic Methods by Wiley-Interscience, 1989; the text Advanced Organic Chemistry, 5th edition, by Jerry March, New York: 2001, Wiley-Interscience; or the Handbook of Heterocyclic Chemistry, by Alan R. Katritzky, London: Pergamon Press Ltd, 1985, to name a few. Alternatively, a skilled artisan may find methods useful for preparing the invention compounds in the chemical literature by searching widely available databases such as, for example, those available from the Chemical Abstracts Service, Columbus, Ohio, or MDL Information Systems GmbH (formerly Beilstein Information Systems GmbH), Frankfurt, Germany.
Preparations of the compounds of the present invention may use starting materials, reagents, solvents, and catalysts that may be purchased from commercial sources or they may be readily prepared by adapting procedures in the references or resources cited above. Commercial sources of starting materials, reagents, solvents, and catalysts useful in preparing invention compounds include, for example, The Aldrich Chemical Company, and other subsidiaries of Sigma-Aldrich Corporation, St. Louis, Mo., BACHEM, BACHEM A.G., Switzerland, or Lancaster Synthesis Ltd, United Kingdom.
Reagents for Organic Synthesis, by Fieser and Fieser, New York, John Wiley and Sons, Inc., 2000; Comprehensive Organic Transformations, by Richard C. Larock, VCH Publishers, Inc., New York, 1989; the series Compendium of Organic Synthetic Methods by Wiley-Interscience, 1989; the text Advanced Organic Chemistry, 5th edition, by Jerry March, Wiley-Interscience, New York 2001; and the Handbook of Heterocyclic Chemistry, by Alan R. Katritzky, Pergamon Press Ltd., London, 1985 are hereby incorporated by reference.
The compounds of the invention are prepared by methods well known to those skilled in the art of organic chemistry. The compounds of Formula I are prepared utilizing commercially available starting materials, or reactants that are readily prepared by standard organic synthetic techniques. A typical synthesis of the invention compounds of Formula I is shown in Scheme 1 below. The first step in Scheme 1 comprises reacting a tricyclic aromatic or heteroaromatic sulfonyl chloride (1) with a substituted thiomorpholine carboxylic acid ester (2). These reactants are generally combined in approximately equimolar quantities in a mutual organic solvent such as dichloromethane, and in the presence of an acid scavenger such as triethylamine. Generally, the reaction is substantially complete within about 2 to 8 hours when carried out at a temperature of about 20xc2x0 C. to 60xc2x0 C. The product, a sulfonamide ester of Formula I (3), can be isolated if desired by removing the reaction solvent by evaporation; and can be purified if desired by recrystallization from solvents such as ethyl acetate and hexane. The sulfonamide ester (3) is next hydrolyzed by reaction with a strong acid such as trifluoroacetic acid, generally in the presence of a free radical scavenger. such as anisole. The sulfonamide acid (4) is generally isolated by simply removing the reaction solvent, and it can be crystallized or chromatographed if desired. The sulfonamide carboxylic (4, where X is OH) acid can be converted to the hydroxamic acid (5, where X is NHOH) by reaction with oxalyl chloride to form the corresponding acid chloride in situ, and then reaction with excess hydroxylamine in the presence of a base such as sodium bicarbonate.
The thiomorpholines of Formula I wherein Y is S are readily converted to the corresponding sulfoxides and sulfones (where Y is SO and SO2) by oxidation with a peracid such as peracetic acetic acid or metachloroperbenzoic acid. This is shown in Scheme 1 (5 to 5). 
The invention compounds of Formula I are ideally suited to synthesis by general combinatorial methodologies. Schemes 2 and 3 illustrate the use of resin supports to facilitate the rapid synthesis of invention compounds. As shown in Scheme 2, a tricyclic-thiomorpholine carboxylic acid (4) is reacted with an acylating agent such as a benzoyl halide to form a mixed anhydride, which is then reacted in situ with a solid resin (e.g., a polystyrene resin xe2x80x9cPSxe2x80x9d such as a commercially available Wang resin) through the oxygen atom to provide a tricyclic-thiomorpholine carboxylic acid bound to a resin support (compound 8 in Scheme 2). Functional groups at other sites in the molecule (e.g., R3 and R4) can be modified by standard methods to provide invention compounds. For example, when R3 of Formula I compounds is a nitro group, it is readily reduced by reaction with a standard reducing agent such as tin chloride to provide the corresponding amino analog (8). The amino group can be acylated by reaction with a common acylating agent such as an acid chloride to give an N-aryl analog of Formula I (a). Alternatively, the amino group can be reacted with an isocyanate RNCO to give ureas of Formula I (10). The tricyclic-thiomorpholine carboxylic acid is readily liberated from the Wang resin by reaction with a strong acid such as trifluoroacetic acid (to give 9 or 10). 
Scheme 3 illustrates the use of a hydroxylamine resin to prepare hydroxamic acids of Formula I (X=NHOH). A tricyclic-thiomorpholine carboxylic acid (4 where X=OH) is first activated at the carboxy group by reaction with a peptide coupling reagent such as dicyclohexylcarbodiimide (DCC) or 1,3-diisopropylcarbodiimide. The activated tricyclic-thiomorpholine carboxylic acid is then reacted with a hydroxylamine resin, generally in the presence of a base such as 4-dimethylaminopyridine (DMAP), to form the resin-bound hydroxamic acid analog (11). Modifications at other sites in the molecule can be carried out as described above in Scheme 2 (nitro groups reduced to amino groups, amino groups alkylated or acylated, etc). Following such modifications, the tricyclic-thiomorpholine hydroxamic acid is readily liberated from the resin by simple acid hydrolysis, for example by reaction with trifluoroacetic acid or the like. 
Scheme 4 illustrates the further modification of ring substituents or the tricyclic portion of the compounds of Formula I. The scheme starts with a halo (Br) substituted tricyclic analog that is carbomylated by reaction with carbon monoxide in the presence of a suitable catalyst to produce an alkoxycarbonyl substituted analog. The alkoxycarbonyl group is reduced to a hydroxymethyl group by reaction with a reducing agent such as sodium borohydride. The hydroxymethyl group is converted to a mesyloxymethyl group by reaction with methanesulfonyl chloride (MSCl). The mesyloxy group is readily displaced by reaction with a nucleophile such as an amine (HNR5R6) to afford various invention compounds of Formula I. As described above, the thiomorpholine carboxylic acids (X=OH) are readily converted to hydroxamic acids (X=NHOH) by reaction with hydroxylamine, or the entire foregoing sequence can be carried out on a hydroxylamine resin as described in Scheme 3. 
During the synthesis of some of the invention compounds, it may be desirable to protect reactive functional groups such as hydroxy, amino, and carboxylic groups, so as to avoid unwanted side reactions. The use of protecting groups in synthetic organic chemistry is well-established and is fully described by Greene and Wuts in xe2x80x9cProtecting Groups in Organic Synthesisxe2x80x9d (John Wiley and Son Press, 3rd ed). Examples of common amino protecting groups include acyl groups such as formyl and acetyl, and arylalkyl groups such as benzyl. Typical hydroxy protecting groups include ether forming groups such as methyl and ethyl, and acyl groups such as acetyl and tert-butoxycarbonyl (tBOC). Carboxylic acids generally are protected as esters, for example 2,2,2-trichloroethyl and benzyl. These protecting groups are readily cleaved by standard methods when desired.
Sulfoxides and sulfones of Formula I, wherein n is 1 or 2, are prepared by oxidation of the corresponding sulfides with one or two equivalents of an oxidizing agent such as peracetic acid or meta-chloroperbenzoic acid.
The following detailed examples further illustrate the synthesis of typical invention compounds of Formula I. The examples are representative only and are not to be construed as limiting the invention in any respect. All references cited herein are incorporated by reference.